Environment and Health Department, Istituto Superiore di Sanita', Viale Regina Elena 299, 00161 Rome, Italy.
Mutagenesis. 2013 Jan;28(1):107-16. doi: 10.1093/mutage/ges059. Epub 2012 Nov 6.
The study of the chemical carcinogenesis mechanisms and the design of efficient prevention strategies and measures are of crucial importance to protect human health. The long-term carcinogenesis bioassays have played a central role in protecting human health, but for ethical and practical reasons their use is dramatically diminishing, and the genotoxicity short-term tests have taken the pivotal role in the pre-screening of carcinogenicity. However, there is evidence that this strategy is not sensitive enough to detect all genotoxic carcinogens and it cannot detect nongenotoxic carcinogens. In a previous article, we have shown that an integrated strategy consisting of the in vitro Ames and Syrian Hamster Embryo cells transformation assays, combined with structure-activity relationships, is a valid alternative to the present pre-screening strategies. Here, we expand the previous investigation by (i) including results of cell transformation assays on inorganics, together with an additional assay (Bhas 42), and (ii) considering new structural alerts for nongenotoxic carcinogenicity. We also present a new analysis on global relationships between toxicological endpoints. The new results confirm that the previously proposed integrated, alternative strategy is an efficient tool to identify both genotoxic and nongenotoxic carcinogens, with an estimated 90-95% sensitivity.
研究化学致癌机制和设计有效的预防策略和措施对于保护人类健康至关重要。长期致癌生物测定在保护人类健康方面发挥了核心作用，但由于伦理和实际原因，其使用正在大幅减少，而遗传毒性短期测试在致癌性的预筛选中占据了关键地位。然而，有证据表明，这种策略不够敏感，无法检测到所有遗传毒性致癌物质，也无法检测到非遗传毒性致癌物质。在之前的一篇文章中，我们已经表明，由体外艾姆斯和叙利亚仓鼠胚胎细胞转化测定组成的综合策略，结合结构-活性关系，是目前预筛选策略的有效替代方法。在这里，我们通过（i）将无机物的细胞转化测定结果以及（ii）考虑新的非遗传毒性致癌性结构警报纳入到之前的研究中来扩展了先前的调查。我们还对毒性终点的全球关系进行了新的分析。新的结果证实，之前提出的综合替代策略是识别遗传毒性和非遗传毒性致癌物质的有效工具，估计有 90-95%的灵敏度。
